Abstract: Anti-mitotic drugs are highly desirable chemotherapy drugs for cancer treatment. Traditional anti-mitotic drugs destroy microtubule dynamics by depolymerizing or stabilizing microtubules to kill the overactive cancer cells. Even though these anti-mitotic drugs have achieved great success, they face two significant issues: 1) Serious side effects; and 2) Strong drug resistance for some types of cancers. To overcome these two issues, kinesins are recently found to be ideal alternative drug targets. While microtubules provide the scaffold for mitosis, it is the interaction of kinesins with microtubule that is responsible for mitotic separation. Moreover, different types of kinesins are responsible for different microtubule functions, allowing for the possible design of drugs specific to mitosis with fewer side effects. Recent experimental works have been performed to reveal mechanisms of kinesin motility successfully. However, many kinesins? mechanisms at the atomic level are still missing in current experimental approaches due to the limitations of resolutions, both in time and in length. Computational works can bridge the gap between atomic details and the resolutions of current experimental approaches. However, simulations for kinesins are extremely challenging due to the large size of kinesin and microtubule system. Based on fast improvements of algorithms in recent years, the PI will develop a large-scale simulation package that is capable of simulating large kinesin-microtubule complexes accurately. This package will be applied to reveal the important mechanisms for kinesins? binding and motility features, which will shed light on kinesin targeting anti-mitotic drug design. The PI has extensive experience of software developments in the areas of protein-protein interactions, electrostatic calculations, binding energy calculations, pKa calculations, and large-scale simulations. Besides, the PI also has gained rich experience of studying kinesins and other molecular motors. The PI?s recent computational woks have revealed that the interaction between kinesin motor domains and the microtubule is an important factor for kinesin?s motility features. And disease mutations on kinesins show strong tendency of electrostatic force changes between kinesins and microtubules. Therefore, investigating kinesins using accurate and comprehensive computational approaches is a very promising direction to understand the mechanisms of kinesins and discover new kinesin targeting anti-mitotic drugs. Besides mitotic kinesins, mutations and defects on other kinesins are also responsible for neurological disorders and serious diseases such as Alzheimer, Huntington, Parkinson disease and many others. The large-scale simulation package developed in this work will also help to discover novel treatments of those diseases. Furthermore, this package will solve the scale limitation issue of traditional simulation packages and therefore can be widely used to study complex biological systems, such as the dynein-microtubule complex, viral capsid assembly, G-proteins systems on the membrane, and many others.